The gammaretroviruses represent a group of mammalian oncogenic retroviruses typically associated with the long-latency induction of leukemia and lymphoma in the natural host. Feline leukemia virus (FeLV), a naturally occurring gammaretrovirus, is found in nature not as a single genomic species but as a genetically complex family of closely related viruses. The consequence of this variation is a genetically diverse virus population that is continuously shaped by selective pressures in vivo and from which variants arise as predominant species. We previously described an isolate of FeLV, termed FeLV-945, as the predominant species in non-T-cell diseases in a geographic cluster of naturally infected animals. Previous studies demonstrated distinctive biological properties of the unique LTR and SU gene characteristic of FeLV-945. These sequence elements were shown to confer a replicative advantage to the virus, to alter interactions with the host cell receptor, and to act as determinants of a novel disease spectrum. Studies are proposed in three Specific Aims to determine their role and mechanisms of action in infection and pathogenesis. Aim 1 proposes to determine the roles of the unique LTR and SU gene of FeLV-945 in disease determination in the natural host. Experiments will be performed to determine whether the FeLV-945 LTR confers a replicative advantage in vivo, and how the receptor-binding properties of FeLV-945 SU influence disease progression. Aim 2 proposes to explore the mechanism of initial apoptotic crisis in hematopoietic progenitors and the subsequent emergence of a surviving population. These studies will utilize a tissue culture model of early hematopoietic progenitor cell differentiation to test a novel hypothesis about the role of p53 and its suppression early in the disease process. Aim 3 proposes to investigate the mechanisms by which infection alters the differentiation of hematopoietic progenitors early in the disease process. In particular, experiments will focus on the mechanism by which infection alters B-lymphoid cell differentiation. Relevance of the Project to Public Health: The proposed analysis of FeLV-mediated disease induction offers a rare opportunity to study mechanisms of pathogenesis in an outbred mammalian host during infection with a natural pathogen. Further, the proposed work is important for understanding the early stages of the induction of malignancy by examining the process in an animal model.